The hippocampus, amygdala, and ventral anterior cingulate are each implicated in the pathophysiology of mood disorders. The volume of the subiculum of the hippocampus is abnormally decreased in MDD and bipolar disorder. Subtle decreases in hippocampal volume were previously reported by some MRI studies of mood disorders, although many other studies were unable to confirm this difference. Two studies of the hippocampus performed post mortem provided clues that the reduction in volume may be confined to only discreet subregions of the hippocampus, namely the subiculum and the adjacent CA1 region. The subiculum is known to play major roles in guiding reward-directed behavior and in modulating endocrine responses to stress, and is the portion of the hippocampus that shares the heaviest anatomical connections with other brain regions implicated in regulating emotional behavior. A method for imaging the human brain at a very high spatial resolution, developed by a collaboration between NIMH and NINDS, permitted reliable volumetric measures of the subiculum and adjacent CA1 cortex. Application of this technique revealed a marked reduction in the volume of the subiculum exists in bipolar disorder, and demonstrated this abnormality can be noninvasively detected using MRI. A paper is now in preparation describing this finding, and these results have been reported at two international scientific meetings. Secondly, the amygdala has an abnormal reduction of glial cells in major depressive disorder (MDD). Glial cells were previously shown to be decreased in other brain regions of the prefrontal cortex which share extensive anatomical connections with the amygdala in both MDD and bipolar disorder. The glial cells play a variety of important roles in assisting the function of the neurons, the cells responsible for carrying signals from one brain region to another. Working in collaboration with researchers at Washington University, we were able to show that the abnormal reduction in glia in the amygdala specifically involves oligodendrocytes, which play major roles in maintaining the communication across connections between neurons. This abnormality could thus interfere with the normal functioning of the amygdala, which plays major roles in the regulation of emotional behavior. The amygdala plays a major role in organizing and regulating the behavioral, autonomic and endocrine responses to threat or stress, and the emotional inferences that occur in response to sad or anxious facial expressions or statements. Using high resolution images obtained on high magnetic field strength magnets at the NIH, we were able to show that the amygdala is reduced in volume by about 20% in both currently depressed subjects with recurrent major depressive disorder (MDD) and in currently remitted subjects with MDD. In contrast, The abnormal reduction in volume did not extend to patients with bipolar disorder, consistent with the post mortem data described above. This finding is being reported at an international scientific meeting during the Winter, and a manuscript is in preparation describing these results. During this past one year we used high resolution MRI images acquired on a high field strength magnet to investigate cerebral volumes in mood disorders. Images were obtained in 28 currently depressed subjects with MDD, 36 currently remitted subjects with MDD, 33 subjects with bipolar disorder, 18 subjects with PTSD and 56 healthy controls. Comparisons across groups showed that the volumes of the subiculum of the hippocampus are decreased in bipolar disorder, but not in the other mood or anxiety disordered groups (ms. in preparation). The volume of the remainder of the hippocampus was decreased in both the depressed and the remitted unipolar depressives (paper submitted) and the PTSD subjects (manuscript in preparation), but not in the bipolar subjects. The volumes of the amygdala were decreased in both depressed and remitted MDD subjects (manuscript submitted). In addition the white matter adjacent to the amygdala was smaller in the MDD groups than the controls. In bipolar disorder, the volumes were smaller only in the subgroup who had not recently been treated with mood stabilizers which show neurotrophic effects in rodents (lithium, divalproex). In addtion, the infralimbic cortex volume was measured. This region's volume is trending to be decreased in currently depressed MDD and bipolar disorder samples, but is increased in PTSD, relative to healthy controls (in preparation).